Our studies have found that certain types of recombinant human interferon can increase the expression of tumor antigens on the surface of human carcinoma cells. Treatment of human breast or colon carcinoma cells with leukocyte clone A increases the binding of several monoclonal antibodies to 3 surface tumor antigens. Other human tumor cells (e.g. melanoma) and normal fibroblasts that do not express these antigens remain negative after treatment with up to 10,000 units of interferon. Other clones of human leukocyte interferon exert a wide range of activities for both antiproliferation and enhancement of surface antigen expression. Clones of the human breast carcinoma cell line, MCF-7, were examined for their responsiveness to human leukocyte clone A interferon. Three of 10 MCF-7 clones were unresponsive to the interferon-mediated increase of surface antigen expression. Upon examination of the number and affinity of the surface interferon receptors, no difference was detected between the responsive and nonresponsive cloned cell lines. These findings indicate that two biological events of human leukocyte interferon, antiproliferation and enhancement of surface antigens, can be functionally separated. Furthermore, the data suggest that additional transcriptional and/or post-translational events are required for the increase in tumor antigen expression induced by interferon. Such findings implicate the possible use of recombinant leukocyte interferon as an adjunct to overcome tumor cell heterogeneity. These studies may also lead to an increase in the efficiency of monoclonal antibodies for localization and treatment of human carcinomas.